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1.
Cell Rep ; 23(5): 1435-1447, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29719256

RESUMO

There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacina BCG/farmacologia , Proteínas de Membrana/imunologia , Mycobacterium tuberculosis/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Vacina BCG/imunologia , Modelos Animais de Doenças , Imunidade Celular/efeitos dos fármacos , Camundongos , Camundongos Knockout , Células Th1/imunologia , Células Th1/patologia , Células Th17/patologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacocinética
2.
Cell Rep ; 25(11): 3074-3085.e5, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30540940

RESUMO

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Animais , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Relação Dose-Resposta Imunológica , Resistencia a Medicamentos Antineoplásicos , Hematopoese , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas S100/administração & dosagem , Proteínas S100/imunologia
3.
Org Lett ; 17(13): 3268-71, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26087830

RESUMO

Reductive lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.


Assuntos
Compostos Heterocíclicos com 2 Anéis/síntese química , Nitrilas/química , Compostos Organometálicos/química , Compostos de Espiro/síntese química , Alquilação , Técnicas de Química Combinatória , Ciclização , Compostos Heterocíclicos com 2 Anéis/química , Estrutura Molecular , Compostos de Espiro/química , Estereoisomerismo , Termodinâmica
4.
Cell Rep ; 11(7): 1018-30, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25959818

RESUMO

Spontaneous tumor-initiated T cell priming is dependent on IFN-ß production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-ß expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Neoplasias Experimentais/imunologia , Nucleotídeos Cíclicos/farmacologia , Microambiente Tumoral/imunologia , Animais , Antineoplásicos/síntese química , Western Blotting , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Técnicas de Inativação de Genes , Humanos , Macrófagos , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Nucleotídeos Cíclicos/síntese química , Reação em Cadeia da Polimerase , Transfecção , Xantonas/farmacologia
5.
Sci Transl Med ; 7(283): 283ra52, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25877890

RESUMO

Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.


Assuntos
Antineoplásicos/química , Vacinas Anticâncer/química , Proteínas de Membrana/agonistas , Receptor de Morte Celular Programada 1/metabolismo , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Citosol/metabolismo , Células Dendríticas/citologia , Feminino , Humanos , Interferon gama/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Monócitos/citologia , NF-kappa B/metabolismo , Transplante de Neoplasias , Fosfatos/química , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT6/metabolismo
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